The invention relates to novel sulfonylaminocarboxylic acids, processes for their preparation and use thereof as pharmaceuticals for the treatment of connective tissue disorders.
Patent applications EP 0 606 046, WO 95/35276 and WO 96/27583 describe arylsulfonamidohydroxamic acids and their action as matrix metalloproteinase inhibitors. Specific arylsulfonamidocarboxylic acids are used as intermediates for the preparation of thrombin inhibitors (EP 0 468 231) and aldose reductase inhibitors (EP 0 305 947). Patent application EP 0 757 037 also describes the action of sulfonylaminocarboxylic acid derivatives as metalloproteinase inhibitors. It is also known to those skilled in the art that the arylsulfonyl group has proven usefulness as an effective protective group of the amino function of xcex1-aminocarboxylic acids (R. Roemmele, H. Rapoport, J. Org. Chem. 53 (1988) 2367-2371).
In the attempt to find efficacious compounds for the treatment of connective tissue disorders, it has now been found that the sulfonylaminocarboxylic acids according to the invention are strong inhibitors of matrix metalloproteinases. Particular value is placed here on the inhibition of stromelysin (matrix metalloproteinase 3) and of neutrophil collagenase (MMP-8), since both enzymes are substantially involved, as important constituents of the cartilaginous tissue, in the degradation of the proteoglycans (A. J. Fosang et al., J. Clin. Invest. 98 (1996) 2292-2299).
The invention therefore relates to compounds of formula (I) 
or stereoisomeric forms of the compound of formula (I), or a physiologically tolerable salt of the compound or the stereoisomeric forms of the compound of formula (I), where
R1 is 1. phenyl,
2. phenyl, which is mono- or disubstituted by
2.1. (C1-C6)-alkyl, which is linear, cyclic, or branched,
2.2. hydroxyl,
2.3. (C1-C6)-alkyl-C(O)xe2x80x94Oxe2x80x94,
2.4. (C1-C6)-alkyl-Oxe2x80x94,
2.5. (C1-C6)-alkyl-Oxe2x80x94(C1-C4)-alkyl-Oxe2x80x94,
2.6. halogen,
2.7. xe2x80x94CF3,
2.8. xe2x80x94CN,
2.9. xe2x80x94NO2,
2.10. HOxe2x80x94C(O)xe2x80x94,
2.11. (C1-C6)-alkyl-Oxe2x80x94C(O)xe2x80x94,
2.12. methylenedioxo,
2.13. R4xe2x80x94(R5)Nxe2x80x94C(O)xe2x80x94,
2.14. R4xe2x80x94(R5)Nxe2x80x94, or
3. a heteroaromatic ring structure as defined below under 3.1. to 3.15., which is unsubstituted, or substituted by the radicals as defined under 2.1 to 2.14.,
3.1. pyrrole,
3.2. pyrazole,
3.3. imidazole,
3.4. triazole,
3.5. thiophene,
3.6. thiazole,
3.7. oxazole,
3.8. isoxazole,
3.9. pyridine,
3.10. pyrimidine,
3.11. indole,
3.12. benzothiophene,
3.13. benzimidazole,
3.14. benzoxazole, or
3.15. benzothiazole;
R2, R4, and R5 are identical or different and each independently are
1. a hydrogen atom,
2. (C1-C6)-alkyl-,
3. HOxe2x80x94C(O)xe2x80x94(C1-C6)-alkyl-,
4. phenyl-(CH2)nxe2x80x94, in which phenyl is unsubstituted, or mono- or disubstituted by the radicals as defined under 2.1. to 2.14., or is substituted by xe2x80x94NHxe2x80x94C(O)xe2x80x94(C1-C3)-alkyl, and n is the integer zero, 1, or 2, or
5. picolyl, or
6. R4 and R5 together with the ring amino group form a 4- to 7-membered ring, in which one of the carbon atoms is optionally replaced by xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, or xe2x80x94NHxe2x80x94, or in which two adjacent carbon atoms of the 4- to 7-membered ring are part of a benzyl radical;
R3 is 1. a hydrogen atom,
2. (C1-C10)-alkyl, in which alkyl is unsubstituted, or in which a hydrogen atom of the alkyl radical is replaced by xe2x80x94OH,
3. (C2-C10)-alkenyl-, in which alkenyl is linear or branched,
4. R2xe2x80x94Oxe2x80x94(C1-C6)-alkyl-,
5. R2xe2x80x94S(O)nxe2x80x94(C1-C6)-alkyl-, where n is as defined above,
6. R2xe2x80x94S(O)(xe2x95x90NH)xe2x80x94(C1-C6)-alkyl-, 
xe2x80x83in which n is the integer zero, 1, or 2, and W is a nitrogen, oxygen or sulfur atom,
8. phenyl-(CH2)mxe2x80x94, in which m is the integer zero, 1, 2, 3, 4, 5, or 6, xe2x80x94(CH2)mxe2x80x94 is unsubstituted, or a hydrogen atom of xe2x80x94(CH2)mxe2x80x94 is replaced by xe2x80x94OH, and phenyl is unsubstituted, or mono- or disubstituted by
8.1. the radicals as defined under 2.1. to 2.14.,
8.2. xe2x80x94Oxe2x80x94(CH2)m-phenyl, in which phenyl is unsubstituted, or mono- or disubstituted by the radicals as defined under 2.1. to 2.14., and m is the integer zero, 1, 2, 3, 4, 5, or 6, or
8.3. xe2x80x94C(O)xe2x80x94(CH2)m-phenyl, in which phenyl is as defined under 8.2.,
9. heteroaryl-(CH2)mxe2x80x94, in which heteroaryl is as defined under 3.1. to 3.15., m is as defined above, or a hydrogen atom of the xe2x80x94(CH2)mxe2x80x94 chain is replaced by xe2x80x94OH, and heteroaryl is unsubstituted, or mono- or disubstituted by
9.1. the radicals as defined under 2.1. to 2.14.,
9.2. xe2x80x94CH(O),
9.3. xe2x80x94SO2-phenyl, in which phenyl is unsubstituted or is as defined under 8.2. or 8.3., or
9.4. xe2x80x94Oxe2x80x94(CH2)m-phenyl,
10. xe2x80x94(CH2)mxe2x80x94P(O)(OH)xe2x80x94(C1-C3)-alkyl, in which m is as defined above, or
11. R6xe2x80x94C(O)xe2x80x94(C1-C6)-alkyl-, in which
R6 is 1. a hydrogen atom,
2. (C1-C6)-alkyl-, in which alkyl is linear, branched or cyclic,
3. phenyl, in which phenyl is unsubstituted or substituted as described under 2.1. to 2.14.,
4. heteroaryl, in which heteroaryl is as defined under 3.1. to 3.15., is unsubstituted, or is substituted by the radicals as described under 2.1. to 2.14., or is substituted by xe2x80x94(C1-C4)-alkyl-COOH,
5. HOxe2x80x94,
6. R2Oxe2x80x94, in which R2 is as defined above,
7. is R4xe2x80x94(R5 )Nxe2x80x94, in which R4 and R5 are as defined above,
8. heteroaryl-(CH2)mxe2x80x94NHxe2x80x94, in which heteroaryl is as defined under 3.1. to 3.15., or as described under 2.1. to 2.14., and m is as defined above,
9. R4xe2x80x94(R5)Nxe2x80x94NHxe2x80x94, in which R4 and R5 are as defined above, or
10. HOxe2x80x94C(O)xe2x80x94CH(R3)xe2x80x94NHxe2x80x94, in which R3 is as defined above; or
R2 and R3 together form a ring having a ring carboxyl group, composing subformula (II): 
xe2x80x83in which r is the integer zero, 1, 2, or 3, or in which one of the carbon atoms in the ring is replaced by xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, or xe2x80x94(R7)Nxe2x80x94, in which
R7 is 1. a hydrogen atom,
2. (C1-C6)-alkyl,
3. phenyl, in which phenyl is unsubstituted, or is substituted by the radicals as described under 2.1. to 2.14.,
4. benzyl, in which benzyl is unsubstituted, or substituted by the radicals as described under 2.1. to 2.14., or
5. R2Nxe2x80x94C(xe2x95x90NH)xe2x80x94, where R2 has the above defined meaning, or the carbon atoms in the ring of subformula (II) are mono- or poly-substituted by (C1-C6)-alkyl-, phenyl-, phenyl-(CH2)mxe2x80x94 or HOxe2x80x94;
A is a) a covalent bond,
b) xe2x80x94Oxe2x80x94,
c) xe2x80x94CHxe2x95x90CHxe2x80x94, or
d) xe2x80x94Cxe2x95x90Cxe2x80x94;
B is a) xe2x80x94(CH2)mxe2x80x94, in which m has the above defined meaning,
b) xe2x80x94Oxe2x80x94(CH2)p, in which p is the integer from 1, 2, 3, 4, or 5
c) xe2x80x94CHxe2x95x90CHxe2x80x94; and
X is xe2x80x94CHxe2x95x90CHxe2x80x94, an oxygen atom, or a sulfur atom.
A currently preferred compound of formula (I) is where
R1 is 1. phenyl, or
2. phenyl, which is monosubstituted by
2.1. (C1-C6)-alkyl-, in which alkyl is linear, cyclic, or branched,
2.2. xe2x80x94OH,
2.3. (C1-C6)-alkyl-C(O)xe2x80x94Oxe2x80x94,
2.4. (C1-C6)-alkyl-Oxe2x80x94,
2.5. (C1-C6)-alkyl-Oxe2x80x94(C1-C4)-alkyl-Oxe2x80x94,
2.6. halogen,
2.7. xe2x80x94CF3, or
2.8. R4xe2x80x94(R5)Nxe2x80x94;
2R, R4 and R5 are identical or different and each independently are
1. a hydrogen atom, or
2. (C1-C6)-alkyl-;
R3 is 1. (C1-C10)-alkyl-, in which alkyl is linear, branched, or cyclic, alkyl is unsubstituted, or in which a hydrogen atom of the alkyl radical is replaced by xe2x80x94OH,
2. R2xe2x80x94S(O)nxe2x80x94(C1-C6)-alkyl-, in which R2 is (C1-C6)-alkyl- or phenyl-(CH2)n, and n is the integer zero or 1,
3. phenyl-(CH2)mxe2x80x94, in which phenyl is unsubstituted, or mono- or disubstituted by the radicals as described under 2.1. to 2.14., xe2x80x94(CH2)mxe2x80x94 is unsubstituted, or a hydrogen atom of xe2x80x94(CH2)mxe2x80x94 is replaced by xe2x80x94OH, and m is the integer 1, 2, 3, 4, or 5,
4. heteroaryl-(CH2)mxe2x80x94, in which heteroaryl is as defined under 3.3., 3.5., 3.6., 3.9., or 3.11., is unsubstituted, or is substituted by the radicals as defined under 2.1. to 2.14., xe2x80x94(CH2)mxe2x80x94 is unsubstituted, or a hydrogen atom of the xe2x80x94(CH2)mxe2x80x94 chain is replaced by xe2x80x94OH, and m is the integer 1, 2, 3, or 4, or
5. R6xe2x80x94C(O)xe2x80x94(C1-C6)-alkyl-, in which
R6 is 1. xe2x80x94OH,
2. R2Oxe2x80x94, in which R is defined as above,
3. R4xe2x80x94(R5 )Nxe2x80x94, in which R4 and R5 are as defined above, or
4. R4 and R5 together with the ring amino group form a 5- to 6-membered ring in which one of the carbon atoms is optionally replaced by xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, or xe2x80x94NHxe2x80x94 or two adjacent carbon atoms of the 5- to 6-membered ring are part of a benzyl radical,
6. R2 and R3 together form a ring having a ring carboxyl group, of subformula (II), in which n is the integer 1 or 2, and/or one of the carbon atoms in the ring is replaced by xe2x80x94Oxe2x80x94 or xe2x80x94(R7)Nxe2x80x94, in which
R7 is 1. a hydrogen atom,
2. (C1-C6)-alkyl,
3. phenyl, in which phenyl is unsubstituted or substituted as defined under 2.1. to 2.14.,
4. benzyl, in which benzyl is unsubstituted, or substituted as defined under 2.1. to 2.14., or
5. R2Nxe2x80x94C(xe2x95x90NH)xe2x80x94, in which R2 is as defined above, and/or the carbon atoms in the ring of the subformula (II) are mono-substituted by phenyl or xe2x80x94OH;
A is a) a covalent bond or
b) xe2x80x94Oxe2x80x94;
B is a) xe2x80x94(CH2)mxe2x80x94, in which m is the integer zero, 1, or 2; or
b) xe2x80x94Oxe2x80x94(CH2)p, in which p is an integer 1 or 2; and
X is xe2x80x94CHxe2x95x90CHxe2x80x94.
A compound of formula (I) is particularly preferred where
R is 1. phenylor
2. phenyl which is monosubstituted by
2.1. halogen, in particular chlorine or fluorine, or
2.2. R4xe2x80x94(R5)Nxe2x80x94, where R4 and R5 are identical or different and are
2.2.1. (C1-C3)-alkyl or
2.2.2. R4 and R5 together with the ring amino group form a 5- to 6-membered ring in which one of the carbon atoms optionally being replaced by xe2x80x94Oxe2x80x94 or xe2x80x94Nxe2x80x94;
R2 is a hydrogen atom;
R3 is 1. heteroaryl xe2x80x94(CH2)mxe2x80x94, in which heteroaryl is as defined under 3.5, 3.11., or 3.13., and the heteroaryl is unsubstituted, or monosubstituted by the radicals as described under 2.1. to 2.14., and m is the integer 1 or 2, or
2. R6xe2x80x94C(O)xe2x80x94(C2-C3)-alkyl, in which
R6 is 1. xe2x80x94OH,
2. R2xe2x80x94Oxe2x80x94, in which R2 is as defined above or
3. R4xe2x80x94(R5)Nxe2x80x94, in which R4 and R5 are identical or different and are
3.1. a hydrogen atom,
3.2. (C1-C3)-alkyl-,
3.3. phenyl-(CH2)xe2x80x94, where phenyl is unsubstituted, or mono- or disubstituted as defined under 2.1. to 2.14., and n is the integer zero, 1, or 2,
3.4. R4 and R5 together with the ring amino group form a 5- to 6-membered ring, where one of the carbon atoms is optionally replaced by xe2x80x94Oxe2x80x94 or xe2x80x94NHxe2x80x94, or form an indoline radical, or
3.5. HOxe2x80x94C(O)xe2x80x94CH(R3)xe2x80x94NHxe2x80x94, in which R3 is as defined above;
A is a covalent bond;
B is xe2x80x94(CH2)oxe2x80x94, in which o is zero; and
X is xe2x80x94CHxe2x95x90CHxe2x80x94.
The expression xe2x80x9cR4 and R5 together with the ring amino group form a 4- to 7-membered ring in which one of the carbon atoms is optionally replaced by xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, or xe2x80x94NHxe2x80x94xe2x80x9d is understood as meaning radicals which are derived, for example, from azetidine, pyrrole, pyrroline, pyridine, azepine, piperidine, oxazole, isoxazole, imidazole, indoline, pyrazole, thiazole, isothiazole, diazepine, thiomorpholine, pyrimidine or pyrazine. The term xe2x80x9chalogenxe2x80x9d is understood as meaning fluorine, chlorine, bromine or iodine. The term xe2x80x9calkylxe2x80x9d or xe2x80x9calkenylxe2x80x9d is understood as meaning hydrocarbon radicals whose carbon chains are straight-chain or branched. Cyclic alkyl radicals are, for example, 3- to 6-membered monocyclic systems such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. Furthermore, the alkenyl radicals can also contain several double bonds. The starting substances of the chemical reactions are known or one of ordinary skill in the art can easily derive and prepare these starting substances by methods known in the literature.
The invention further relates to a process for the preparation of the compound of formula (I) or a stereoisomeric form of the compound of formula (I) or of a physiologically: tolerable salt of the compound or the stereoisomeric form of the compound of formula (I), which comprises:
a) reacting an aminocarboxylic acid of formula (III), 
xe2x80x83in which R2 and R are as defined in formula (I), with a sulfonic acid derivative of formula (IV), 
xe2x80x83in which R1, A and B are as defined in formula (I) and Y is a halogen atom, imidazolyl or xe2x80x94OR8, in which R8 is a hydrogen atom, (C1-C6)-alkyl, phenyl or benzyl, if appropriate substituted, in the presence of a base or optionally of a dehydrating agent to give a compound of formula (I), or
b) reacting an aminocarboxylic acid ester of formula (V), 
xe2x80x83in which R2, R3 and R8 have the above defined meaning, with a sulfonic acid derivative of formula (IV) under the above defined conditions to give a compound of formula (VI) 
xe2x80x83and converting the compound of formula (VI) into a compound of formula (I) with removal of the radical R8, preferably in the presence of a base or acid, or
c) reacting the compound of formula (VII), 
xe2x80x83where n is the integer zero, 1 or 2, with the aid of a protective group E to give a compound of formula (VIII), 
xe2x80x83converting the compound of formula (VIII) with a sulfonic acid derivative of formula (IV) under the above defined conditions into a compound of formula (IX) 
xe2x80x83and then converting the compound of formula (IX) into the compound of formula (I) by the removal of the protective group E and of the radical R8 with the aid of suitable cleaving reagents.
d) resolving a compound of formula (I), which on account of its chemical structure occurs in enantiomeric forms, prepared by process a), b) or c) into the pure enantiomers by salt formation with enantiomerically pure acids or bases, chromatography on chiral stationary phases or derivatization by means of chiral enantiomerically pure compounds such as amino acids, separation of the diastereomers thus obtained, and removal of the chiral auxiliary groups, or isolating the compound of formula (I) prepared by process a), b), c) or d) either in free form or, in the case of the presence of acidic or basic groups, converting it into physiologically tolerable salts.
Suitable protective groups E used for this purpose are preferably the N-protective groups customary in peptide chemistry, for example, protective groups of the urethane type, benzyloxycarbonyl (Z), t-butoxycarbonyl (Boc), 9-fluorenyloxycarbonyl (Fmoc), allyloxycarbonyl (Aloc) or of the acid amide type, e.g., formyl, acetyl or trifluoroacetyl, and of the alkyl type, e.g., benzyl.
Compounds of formula (III) employed in which R2 is a hydrogen atom and R3 is the characteristic radical of a natural xcex1-amino acid are preferably glycine, alanine, valine, leucine, isoleucine, phenylalanine, tyrosine, tryptophan, serine, threonine, cysteine, methionine, asparagine, glutamine, lysine, histidine, arginine, glutamic acid and aspartic acid. In the case of natural, as well as unnatural, xcex1-amino acids which have a functional group such as amino, hydroxyl, carboxyl, mercapto, guanidyl, imidazolyl or indolyl in the side chain R3, this group can also be protected.
In the case of an imidazole radical in R3, the sulfonic acid derivative of formula (IV) employed for the sulfonamide formation serves, for example, as a protective group of the imidazole nitrogen, which can be removed again, in particular in the presence of bases such as sodium hydroxide solution.
To prepare compounds of formula (I) in which R2 and R3 together form a ring of the substructure II, starting substances of the formula (III) used are, for example, proline, 3- or 4-hydroxyproline, piperidine-2-carboxylic acid, piperazine-2-carboxylic acid and hexahydropyridazine-3-carboxylic acid, it being possible, in particular, for the nitrogen in the 4-position of the piperazine-2-carboxylic acid to be substituted by a protective group Z, for example benzyloxycarbonyl or tert-butyloxycarbonyl as described in process variant c) or by a radical R7.
Starting materials used for the preparation of the sulfonic acid derivatives of formula (IV) are preferably sulfonic acids or their salts of formula (X), for example 
where R9 is a radical as defined under 2.1. to 2.14.
To prepare the arylsulfonic acids of the formulae (Xa) and (Xb), the sulfonation process using concentrated sulfuric acid, optionally in the presence of a catalyst, sulfur trioxide and its addition compounds or halosulfonic acids, such as chlorosulfonic acid, described in Houben-Weyl Methoden der Organischen Chemie [Methods of Organic Chemistry], Volume 9, pp. 450-546, is preferably used. Particularly in the case of the diphenyl ethers of formula (Xb), the use of concentrated sulfuric acid and acetic anhydride as solvents (cf. C. M. Suter, J. Am. Chem. Soc. 53 (1931) 1114), or the reaction with excess chlorosulfonic acid (J. P. Bassin, R. Cremlyn and F. Swinboume; Phosphorus, Sulfur and Silicon 72 (1992) 157) has proven suitable. Sulfonic acids according to the formulae (Xc), (Xd) or (Xe) can be prepared in a known manner by reacting the appropriate arylalkyl halide with sulfites such as sodium sulfite or ammonium sulfite in aqueous or aqueous/alcoholic solution, it being possible to accelerate the reaction in the presence of tetraorganoammonium salts such as tetrabutylammonium chloride.
Sulfonic acid derivatives according to formula (IV) used are in particular the sulfonyl chlorides. For their preparation, the corresponding sulfonic acids, also in the form of their salts such as sodium, ammonium or pyridinium salts, are reacted in a known manner with phosphorus pentachloride or thionyl chloride without or in the presence of a solvent such as phosphorus oxychloride or of an inert solvent such as methylene chloride, cyclohexane or chloroform, in general at reaction temperatures from 20xc2x0 C. up to the boiling point of the reaction medium used.
The reaction of the sulfonic acid derivatives of formula (IV) with the amino acids of formulae (III), (V) or (VII) according to process variants a), b) or c) advantageously proceeds in the manner of the Schotten-Baumann reaction. Suitable bases for this purpose are particularly alkali metal hydroxides such as sodium hydroxide, but also alkali metal acetates, hydrogencarbonates, carbonates and amines. The reaction takes place in water or in a water-miscible or immiscible solvent such as tetrahydrofuran (THF), acetone, dioxane or acetonitrile, the reaction temperature in general being kept at from xe2x88x9210xc2x0 C. to 50xc2x0 C. In the case in which the reaction is carried out in anhydrous medium, tetrahydrofuran or methylene chloride, acetonitrile or dioxane in the presence of a base, such as triethylamine, Nxe2x80x94methylmorpholine, Nxe2x80x94ethyl or diisopropylethylamine is particularly used, possibly in the presence of N,Nxe2x80x94dimethylaminopyridine as a catalyst.
In another variant, the aminocarboxylic acids of the formulae (III), (IV) or (VII) can first be converted into their silylated form with the aid of a silylating agent such as bis-trimethylsilyltrifluoroacetamide (BSTFA) and they can then be reacted with sulfonic acid derivatives to give compounds of formula (I).
The physiologically tolerable salts of the compounds of formula (I) capable of salt formation, including their stereoisomeric forms, are prepared in a manner known in the art. With basic reagents such as hydroxides, carbonates, hydrogencarbonates, alcoholates and also ammonia or organic bases (e.g., trimethyl- or triethylamine, ethanolamine or triethanolamine), or, alternatively, basic amino acids (e.g., lysine, ornithine or arginine), the carboxylic acids form stable alkali metal, alkaline earth metal or optionally substituted ammonium salts. If the compounds of formula (I) have basic groups, stable acid addition salts can also be prepared with strong acids. Those suitable for this purpose are both inorganic and organic acids such as hydrochloric, hydrobromic, sulfuric, phosphoric, methanesulfonic, benzenesulfonic, p-toluenesulfonic, 4-bromobenzenesulfonic, cyclohexylamidosulfonic, trifluormethylsulfonic, acetic, oxalic, tartaric, succinic or trifluoroacetic acid.
The invention also relates to pharmaceuticals comprising an efficacious amount of at least one compound of formula (I), a stereoisomeric form of the compound of formula (I), or of a physiologically tolerable salt of the compound or stereoisomeric form of the compound of formula (I), together with a pharmaceutically suitable and physiologically tolerable excipient, additive, or other active or inactive compounds and auxiliaries.
On account of the pharmacological properties, the compounds according to the invention are suitable for the prophylaxis and therapy of all those disorders in the course of which an increased activity of matrix-degrading metalloproteinases is involved. These include degenerative joint disorders such as osteoarthroses, spondyloses, chondrolysis after joint trauma or relatively long immobilization of the joint after meniscus or patella injuries or tears of the ligaments. Furthermore, these also include disorders of the connective tissue such as collagenoses, periodontal disorders, wound healing disorders and chronic disorders of the locomotory apparatus such as inflammatory, immunologically or metabolically related acute and chronic arthritides, arthropathies, myalgias and disorders of the bone metabolism. The compounds of formula (I) are furthermore suitable for the treatment of ulceration, atherosclerosis and stenoses. The compounds of formula (I) are furthermore suitable for the treatment of inflammations, carcinomatous disorders, formation of tumor metastases, cachexia, anorexia and septic shock. The pharmaceuticals according to the invention are in general administered orally or parenterally. Transmucosal (such as rectal administration) or transdermal administration is also possible.
The invention also relates to a process for the production of a pharmaceutical, which comprises bringing at least one compound of formula (I) into a suitable administration form using a pharmaceutically suitable and physiologically tolerable excipient and, if appropriate, other suitable active or inactive compounds, additives or auxiliaries.
Suitable solid or pharmaceutical preparation forms are, for example, granules, powders, coated tablets, tablets, (micro)capsules, suppositories, syrups, juices, suspensions, emulsions, drops or injectable solutions and also preparations with protracted release of active compound, in whose preparation customary auxiliaries, such as excipients, disintegrants, binders, coating agents, swelling agents, glidants or lubricants, flavorings, sweeteners and solubilizers are used. Frequently used auxiliaries which may be mentioned are magnesium carbonate, titanium dioxide, lactose, mannitol and other sugars, talc, lactoprotein, gelatin, starch, cellulose and its derivatives, animal and vegetable oils such as fish liver oil, sunflower, groundnut or sesame oil, polyethylene glycol and solvents such as, for example, sterile water and mono- or polyhydric alcohols such as glycerol.
The pharmaceutical preparations are preferably prepared and administered in dose units, each unit as active constituent containing a specific dose of the compound of formula (I) according to the invention. In solid dose units such as tablets, capsules, coated tablets or suppositories, this dose can be up to approximately 1000 mg, with the currently preferred dose being approximately 50 to 300 mg, and in injection solutions in ampoule form up to approximately 300 mg, with the currently preferred dose being approximately 10 to 100 mg.
For the treatment of an adult patient weighing approximately 70 kgxe2x80x94depending on the efficacy of the compounds according to formula (I), daily doses of approximately 20 mg to 1000 mg, preferably approximately 100 mg to 500 mg, of active compound are indicated. Under certain circumstances, however, higher or lower daily doses may be appropriate. The daily dose can be administered both by single administration in the form of an individual dose unit or else of several smaller dose units and by multiple administration of subdivided doses at specific intervals.
1H-NMR spectra have been recorded on a 200 MHz apparatus from Varian, as a rule using tetramethylsilane (TMS) as an internal standard and at room temperature (RT). The solvents used are in each case indicated. As a rule, final products are determined by mass spectroscopic methods (FAB-, ESI-MS). Temperature data in degrees Celsius, RT means room temperature (22-26xc2x0 C.). Abbreviations used are either explained or correspond to the customary conventions.